Impaired mucus detachment disrupts mucociliary transport in a piglet model of cystic fibrosis

Mark J Hoegger; Anthony J Fischer; James D McMenimen; Lynda S Ostedgaard; Alex J Tucker; Maged A Awadalla; Thomas O Moninger; Andrew S Michalski; Eric A Hoffman; Joseph Zabner; David A Stoltz; Michael J Welsh

doi:10.1126/science.1255825

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Impaired mucus detachment disrupts mucociliary transport in a piglet model of cystic fibrosis

Journal article

Peer reviewed

Impaired mucus detachment disrupts mucociliary transport in a piglet model of cystic fibrosis

Mark J Hoegger, Anthony J Fischer, James D McMenimen, Lynda S Ostedgaard, Alex J Tucker, Maged A Awadalla, Thomas O Moninger, Andrew S Michalski, Eric A Hoffman, Joseph Zabner, …

Science (American Association for the Advancement of Science), Vol.345(6198), pp.818-822

08/15/2014

DOI: 10.1126/science.1255825

PMCID: PMC4346163

PMID: 25124441

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Abstract

Lung disease in people with cystic fibrosis (CF) is initiated by defective host defense that predisposes airways to bacterial infection. Advanced CF is characterized by a deficit in mucociliary transport (MCT), a process that traps and propels bacteria out of the lungs, but whether this deficit occurs first or is secondary to airway remodeling has been unclear. To assess MCT, we tracked movement of radiodense microdisks in airways of newborn piglets with CF. Cholinergic stimulation, which elicits mucus secretion, substantially reduced microdisk movement. Impaired MCT was not due to periciliary liquid depletion; rather, CF submucosal glands secreted mucus strands that remained tethered to gland ducts. Inhibiting anion secretion in non-CF airways replicated CF abnormalities. Thus, impaired MCT is a primary defect in CF, suggesting that submucosal glands and tethered mucus may be targets for early CF treatment.

Animals, Newborn

Cilia - physiology

Cystic Fibrosis - physiopathology

Mucociliary Clearance

Cystic Fibrosis Transmembrane Conductance Regulator - physiology

Mucus - secretion

Lung - physiopathology

Exocrine Glands - secretion

Anions - metabolism

Animals

Swine

Methacholine Chloride - pharmacology

Respiratory Mucosa - physiopathology

Respiratory System - physiopathology

Trachea - physiopathology

Disease Models, Animal

Details

Title: Subtitle: Impaired mucus detachment disrupts mucociliary transport in a piglet model of cystic fibrosis
Creators: Mark J Hoegger - Department of Molecular Physiology and Biophysics, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA
Anthony J Fischer - Department of Pediatrics, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA
James D McMenimen - Department of Internal Medicine, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA
Lynda S Ostedgaard - Department of Internal Medicine, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA
Alex J Tucker - Department of Internal Medicine, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA
Maged A Awadalla - Department of Internal Medicine, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA
Thomas O Moninger - Central Microscopy Research Facility, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA
Andrew S Michalski - Department of Internal Medicine, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA
Eric A Hoffman - Department of Internal Medicine, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA. Department of Radiology, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA. Department of Biomedical Engineering, University of Iowa, Iowa City, IA 52242, USA
Joseph Zabner - Department of Internal Medicine, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA
David A Stoltz - Department of Molecular Physiology and Biophysics, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA. Department of Internal Medicine, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA. Department of Biomedical Engineering, University of Iowa, Iowa City, IA 52242, USA. david-stoltz@uiowa.edu michael-welsh@uiowa.edu
Michael J Welsh - Department of Molecular Physiology and Biophysics, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA. Department of Internal Medicine, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA. Howard Hughes Medical Institute (HHMI), University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA. david-stoltz@uiowa.edu michael-welsh@uiowa.edu
Resource Type: Journal article
Publication Details: Science (American Association for the Advancement of Science), Vol.345(6198), pp.818-822
DOI: 10.1126/science.1255825
PMID: 25124441
PMCID: PMC4346163
NLM abbreviation: Science
ISSN: 0036-8075
eISSN: 1095-9203
Publisher: United States
Grant note: P01 HL091842 / NHLBI NIH HHS HL051670 / NHLBI NIH HHS Howard Hughes Medical Institute DP2 HL117744 / NCCDPHP CDC HHS T32 GM007337 / NIGMS NIH HHS HL091842 / NHLBI NIH HHS P01 HL051670 / NHLBI NIH HHS DK054759 / NIDDK NIH HHS P30 DK054759 / NIDDK NIH HHS DP2 HL117744 / NHLBI NIH HHS
Language: English
Date published: 08/15/2014
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Neurology; Radiology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Pulmonary Medicine; Stead Family Department of Pediatrics; Neurosurgery; Internal Medicine
Record Identifier: 9984020615002771

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